HU199286B - Process for producing stabileinjectable pharmaceutical compositions containing 1,4-dihydroxy-5,8-bis/2-/2-hydroxy-ethyl-amino/-ethyl-amino/-antraquinone-dihydro-chloride as activer component - Google Patents

Abstract

This disclosure describes stable injectable pharmaceutical formulations of NOVANTRONE TM .

Description

The present invention relates to a process as an active ingredient

For the preparation of stable injectable compositions containing 1,4-dihydroxy-5,8-bis [2- (2-hydroxyethylamino) ethylamino] -anthraquinone dihydrochloride.

1,4-Dihydroxy-5,8-bis [2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride of formula (1) is known from U.S. Pat. No. 4,197,249. It has already been marketed under the Novantrone brand name in Canada and Europe, and is currently in the US by the Food and Drug Administration. crayfish: ll <'il lialáúú congregation.

This compound is known to undergo oxidative degradation in aqueous solution. This decomposition is much faster in the presence of metal ions such as copper (I), shake (II), iron (II) or iron (in) ions, even if they are present in negligible amounts, i.e. less than 10 ppm. .

In contrast to oral administration, this compound exhibits optimal pharmacological activity in humans upon parenteral (intramuscular, intravenous) administration, so that it is crucial that solutions of this compound remain stable over a prolonged period of time under normal storage conditions.

It has been discovered that under normal conditions of storage, extremely stable injectable aqueous pharmaceutical compositions can be prepared.

1.4-dihydroxy-5,8-thick [2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride, if used

1) contains antioxidants,

2) has a pH within a defined range, and

3) it contains a metal chelating compound.

Sodium metabisulphite has been found to be most effective in antioxidants.

The most effective pH range is between 2.0 and 3.5 and the optimum pH is 3.0.

The most effective chelating agent is a combination of ethylenediaminetetraacetic acid disodium salt and glycine.

Given that the injectable pharmaceutical composition containing 1,4-dihydroxy-5,8-bia2- (2- (2-hydroxyethylamino) -ethylamino) -anthraquinone dihydrochloride is preferably 1-5 mg of active ingredient per milliliter. contains new stable pharmaceutical compositions according to the invention having a pH in the range of 2.0 to 3.5, optimally 3.0 and 0.01-0.10%, optimally 0.05% sodium metabisulfite, Containing from 0.01% to 0.11%, optimally 0.10% disodium salt of ethylenediaminetetraacetic acid and 0.05-0.2% optimally 0.1% glycine.

To demonstrate the increased stability of the novel pharmaceutical compositions of the present invention, the following compositions are prepared and tested.

Formulation # 1

1,4-Dihydroxy-5,8-bisl 2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride 2 mg / ml water for injection (USP *) 100% supernatant air ⁴ - umerikni United States Pharmacopoeia quality

Preparation 2

l, 4-dihydroxy-5,8-bis [2- - (2-Hydroxyethylamino) -ethylamino) -anthraquinone dihydrochloride 2 mg / ml copper (II) ions 7 p.m. water for injection (U.S.P.) 100% fluid overflowing space air pH 5:50

Preparation 3

l, 4-dihydroxy-5,8-bis [2- - (2-Hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride 2 mg / ml Sodium metabisulfite 0.01% Sodium acetate 0.005% glacial acetic acid 0.046% nétrium chloride 0.80% water for injection (U.S.P.) 100% pH 3.5 fluid overflowing space nitrogen

Preparation 4

1,4-dihydroxy-5,8-biszl2- - (2-hydroxyethylamino) - ethylamino] -antrakinon- dihydrochloride 2 mg / ml Sodium metabisulfite 0.05% ethylenediaminetetraacetic tetraecet- acid disodium salt 0.10% glycine 0.10% sodium chloride (isotonic agent) 0.786% water for injection (U.S.P.) 100% PH 3.0 fluid overflowing space below* * - one portion under nitrogen, two others

portion filled with air.

HU 199286 Β

In the following, it will be described that the exemplary No. 4 in FIG. how to prepare the composition.

1) Weigh 45 ml of water for injection into a Pyrex-type glass vessel (for example, see U.S. Pharmacopoeia), cool to 20-27 ° C, purge with nitrogen for 1 hour, and then continue to purge with nitrogen. during the execution of operations until the completion of operation 8.

2) Another Pyrex glass vessel is weighed with 20 ml of water for injection and flushed with nitrogen for one hour. This water will be used later in Step 3 to make a s hydrochloric acid solution, and in Step 4 to make a 10X sodium hydroxide solution,

In step 12 to adjust the final volume.

3) Prepare ΙΟΧ hydrochloric acid solution from concentrated hydrochloric acid (reagent grade) by adding 113 mL of concentrated hydrochloric acid solution to 250 mL of nitrogen-treated water for injection, followed by mixing with a Teflon-coated stirrer until a clear solution is obtained.

The final volume is then adjusted to 500 ml with nitrogen-injected water for injection.

4) Prepare ΙΟΧ sodium hydroxide solution by dissolving 50 g of reagent grade sodium hydroxide in a sufficient quantity of nitrogen-treated water for injection to give a final volume of 500 ml. Dissolution is performed while stirring with a Teflon-coated mixer.

5.) Dissolve 50 g of ethylenediaminetetraacetic acid disodium salt in water for injection in a Pyrex glass vial with nitrogen gas and stir until the solution is clear.

6) Add 50 g of glycine to the solution obtained in Step 5 and mix with Teflon-coated stirrer until no clear solution is formed.

7) To the solution obtained in step 6 is added 393 g of a sodium chloride grade of the United States Pharmacopoeia, followed by mixing with a Teflon-coated stirrer until a clear solution is obtained.

8) Slowly add ΙΟΧ hydrochloric acid solution to the solution obtained in Step 7 in small portions under constant stirring until the pH is 3.0 * 0.1. If the pH drops below 3.0, the 3.0 is reset to 0.1 by the addition of 15 small portions of ΙΟΧ sodium hydroxide solution. It is important to measure the solution ρ érték with two freshly calibrated pH meters. Prior to the measurement, the electrodes are allowed to equilibrate for at least five minutes to adjust to a stable pH.

² θ 9-a) At the end of step 8, immediately before the addition of sodium metabisulphite, the flow of nitrogen is stopped, but the nitrogen pad is maintained.

9-b) 25 g of sodium metabisulphite are added to the solution obtained in Step 8, followed by stirring with a Teflon-coated stirrer until a clear solution is obtained.

10) Suspend 1,4-dihydroxy-5,8-bis ((2-hydroxyethylamino) -ethylamino) -anthraquinone dihydrochloride in a glove manipulator and add the powder as shown in 9-b. Stirring is carried out until a clear solution is obtained.

11) The final volume is adjusted to 50 ml with nitrogen-treated water for injection.

12) Check pH and adjust to pH 3.0 if necessary.

The results of the stability tests are as follows:

Number of preparation ampoule size Supernatant fluid Temperature ° C * Percentage of initial active ingredient content 1 day 2 weeks 3 weeks 4 weeks 6 weeks 8 weeks First 10 ml air 56 88 84.5 72 Second 10 ml air 56 13 Third 10 ml nitrogen 56 90 85 Third 2 ml nitrogen 42 96 93 Third 2 ml nitrogen 56 85 72 4th 10 ml nitrogen 56 99 4th 2 ml nitrogen 42 98.6 97.9 4th 10 ml air 56 98 97.6 5th 10 ml air 42 98 97.5 5th 10 ml nitrogen 56 99 98.4

The drug content is determined by HPLC.

Parameters:

Column: A column of 3.9 mm in diameter and 300 mm in length, supplied by Waters Associates, Inc., packed with .pBondapak Phenyl ';

mobile phase: a mixture of 750 ml water, 250 ml acetonitrile and 2 ampoules of 1-heptanesulfonic acid (final concentration: 0.01 mol);

flow rate: 3 ml / min;

detector: 254 nm ultraviolet light, 1 cm cuvette length;

column temperature: ambient, about 25 ° C; injection volume: 20 microliters.

The above results clearly demonstrate the superiority of the pharmaceutical formulations of the present invention over the prior art formulation and the simple aqueous solution of said active ingredient.

As with other anticancer agents, the dose of 1,4-dihydroxy-5,8-bis [2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride depends on the specific surface area of the patient's body and the disease. should be selected depending on your condition. It is extremely advantageous both in terms of cost and marketability that the active ingredient is 1,4-dihydroxy-5,8-bis [2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride in small containers, for example, in 2 ml ampoules. However, since the space above the liquid ampoules is relatively larger compared to the larger ampoules, the stability of the product becomes critical in small ampoules, such as 2 ml. It is therefore important to note that the compositions of the present invention have been found to be more advantageous than the known compositions in both small volume and relatively larger volume ampoules.

To further demonstrate the stability of the compositions of the present invention, the following composition was prepared.

Preparation S.

1,4-dihydroxy-5,8-bis [2- (2- - hydroxyethylamino) ethyl dihydro-amino-anthraquinone k chloride 2 mg / ml ethylenediaminetetraacetic tetraecetsav- disodium salt 0.10% Sodium metabisulfite 0.04% glycine 0.10% sodium chloride (isotonic agent) 0.60% suitable for injection viz (U.S.P.) 100% pH 3.0

For both formulation No. 5 and formulation No. 1 as previously mentioned, 6 p.p.m. Copper (II) ions are added and the compositions are stored at 56 ° C for four weeks. The tests carried out at this time show that the active ingredient content of Formulation 1 decreases by 98% within 2 days, while the content of Formulation 5 remains at 98.6% after four weeks.

Claims (2)

A process for the preparation of a pharmaceutical composition containing 1-4 mg / ml of 1,4-dihydroxy-5,8-bis [2- (2-hydroxyethylamino) -ethylamino] -anthraquinone dihydrochloride, preferably 2 mg / ml. in the form of an isotonic solution, wherein the pH of the composition is adjusted to between 2.0 and 3.5, and 0.01-0.10% sodium metabisulfite, 0.01-0.11% ethylene diamine tetraacetic acid disodium salt and 0.05-0.20% glycine are added. 2. The process of claim 1, wherein the sodium metabisulfite, ethylenediaminetetraacetate disodium salt, and glycine are each present at a concentration of 0.05%, 0.10% and 0.10%, respectively.